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Biomedical subjects

S B Brown

Publications and source records attributed to S B Brown.

At least 19 recordsLinked to original sources
PubMed2005

Phthalocyanine-mediated photodynamic therapy induces cell death and a G0/G1 cell cycle arrest in cervical cancer cells.

We have developed a series of novel photosensitizers which have potential for anticancer photodynamic therapy (PDT). Photosensitizers include zinc phthalocyanine tetra-sulphonic acid and a family of derivatives with amino acid substituents of varying alkyl chain length and degree of branching. Subcellular localization of these photosensitizers at the phototoxic IC(50) concentration in human cervical carcinoma cells (SiHa Cells) was similar to that of the lysosomal dye Lucifer Yellow. Subsequent nuclear relocalization was observed following irradiation with 665nm laser light. The PDT response was characterized using the Sulforhodamine B cytotoxicity assay. Flow cytometry was used for both DNA cell cycle and dual Annexin V-FITC/propidium iodide analysis. Phototoxicity of the derivatives was of the same order of magnitude as for tetrasulphonated phthalocyanine but with an overall trend of increased phototoxicity with increasing amino acid chain length. Our results demonstrate cell death, inhibition of cell growth, and G(0)/G(1) cell cycle arrest during the phthalocyanine PDT-mediated response.

Cell Cycle↗
PubMed2004

Effects of water-borne 4-nonylphenol and 17beta-estradiol exposures during parr-smolt transformation on growth and plasma IGF-I of Atlantic salmon (Salmo salar L.).

4-Nonylphenol (4-NP) is an endocrine disrupting substance (EDS) capable of mimicking the action of 17beta-estradiol (E2). It has been hypothesized that 4-NP in a pesticide formulation is linked to historical declines in Canadian Atlantic salmon (Salmo salar L.) populations, with effects being related to exposure during parr-smolt transformation (PST). To test this hypothesis, Atlantic salmon smolts were exposed to pulse-doses of water-borne 4-NP (20 ug/l), sustained doses of water-borne E2 (100 ng/l) (positive control), or ethanol vehicle (negative control) in mid-May during the final stages of PST. Individually tagged smolts were then sampled at three times (June, July and October) to monitor subsequent growth in sea water and plasma insulin-like growth factor I (IGF-I) concentrations. Smolt weights and plasma IGF-I concentrations were both affected by E2 and 4-NP. The effects of E2 and 4-NP on mean smolt weights were most prominent in July and October [E2 (*98.1 +/- 2.8, *242.3 +/- 10.6 g), 4-NP (*102.1 +/- 3.1, 255.7 +/- 9.5 g), controls (112.5 +/- 2.8, 282.3 +/- 8.8 g)] (P < 0.05), while their effects on mean plasma IGF-I concentrations were most prominent in June and October [E2 (15.0 +/- 1.9, 28.4 +/- 1.8 ng/ml), 4-NP (*14.8 +/- 1.9, *21.6 +/- 1.7 ng/ml), controls (20.0 +/- 1.1, 31.1 +/- 2.0 ng/ml)] (P < 0.05). Additionally, results suggest that the mechanisms of action of E2 and 4-NP involve disruption in the GH/IGF-I axis, and that they may be different from each other. The effects of E2 and 4-NP on growth and plasma IGF-I concentrations observed in this study are ecologically significant because they evoke concerns for successful growth and survival of wild salmon smolts exposed to low levels of estrogenic substances that may occur from current discharges into rivers supporting sea-run salmon stocks.

Animals↗
PubMed2004

Comparison of high- vs low-dose 5-aminolevulinic acid for photodynamic therapy of Barrett's esophagus.

BACKGROUND: Barrett's esophagus is the major risk factor for esophageal adenocarcinoma, the incidence of which is increasing rapidly in the Western world. Aminolevulinic acid for photodynamic therapy (ALA-PDT) is effective in the treatment of Barrett's esophagus, but controversy exists regarding optimum ALA dosage. The aim of this study was to establish the optimum dosage regime for ALA-PDT for Barrett's esophagus. METHODS: Twenty-five patients with Barrett's esophagus were randomized to receive 30 (low-dose) or 60 (high-dose) mg/kg oral ALA at 4 or 6 h or 30 mg/kg in two fractions 4 and 6 h before PDT. PDT was standardized using red (635 nm) light. Biopsy specimens were taken for protoporphyrin IX (PpIX) quantification. Endoscopy was repeated 4 weeks later. RESULTS: All patients showed a macroscopic response, with squamous re-epithelialization. This response was greatest in the 30 mg/kg and fractionated ALA groups. There was no significant difference in response between dosing 4 or 6 h prior to PDT. Tissue levels of PpIX were similar for all dosage groups and were not predictive of clinical response. Side effects were more common with the higher dose of ALA. CONCLUSION: Low-dose ALA-PDT appears to be a safe protocol for the ablation of Barrett's esophagus.

Administration, Oral↗
PubMed2003

Photodynamic therapy effect of m-THPC (Foscan) in vivo: correlation with pharmacokinetics.

m-Tetra(hydroxyphenyl)chlorin (m-THPC, Foscan, Temoporfin) has an unusually high photodynamic efficacy which cannot be explained by its photochemical properties alone. In vivo interactions are therefore of critical importance in determining this high potency. The pharmacokinetics of m-THPC in a rat tumour model was determined using (14)C m-THPC in an LSBD(1) fibrosarcoma implanted into BDIX rats. The photodynamic therapy (PDT) efficacy was determined at different drug administrations to light intervals and correlated with the tumour and plasma pharmacokinetic data. The plasma pharmacokinetics of m-THPC can be interpreted by compartmental analysis as having three half-lives of 0.46, 6.91 and 82.5 h, with a small initial volume of distribution, suggesting retention in the vascular compartment. Tissues of the reticuloendothelial system showed high accumulation of m-THPC, particularly the liver. PDT efficacy of m-THPC over the same time course seemed to exhibit two peaks of activity (2 and 24 h), in terms of tumour growth delay with the peak at 24 h postinjection correlating to the maximum tumour concentration. Investigation on tumour cells isolated from m-THPC-treated tumours suggested that the peak PDT activity at 2 h represents an effect on the vasculature while the peak at 24 h shows a more direct response. These results indicate that the in vivo PDT effect of m-THPC occurs via several mechanisms.

Animals↗
PubMed2003

The role of light in the treatment of non-melanoma skin cancer using methyl aminolevulinate.

Photodynamic therapy (PDT) is a developing approach to the treatment of cancer and other diseases that involves the use of light to activate photosensitizer molecules. The light energy absorbed by the photosensitizer is transferred to molecular oxygen, which is converted into the highly reactive and cytotoxic species, singlet oxygen. Topical agents such as aminolevulinic acid (ALA) or methyl aminolaevulinate (MAL) may be used for PDT of non-melanoma skin cancers (NMSC) because, in vivo, these agents stimulate the production of porphyrins which act as powerful photosensitisers. This brief review focuses on the use of light to activate MAL, which is now an approved drug (Metvix for certain NMSCs in the European Union. Porphyrins produced by the action of MAL can be activated using red light, which is also capable of deeply penetrating the skin. A number of light sources are available for treatment of NMSC using MAL, including very convenient non-laser sources such as non-coherent filtered lamps and, more recently, sources containing arrays of light-emitting diodes (LEDs). The Aktilite lamp, specifically designed for use with Metvix cream, has an emission spectrum that closely matches the red light absorption profile of PpIX.

Aminolevulinic Acid↗
PubMed2002

Porphyrin accumulation induced by 5-aminolaevulinic acid esters in tumour cells growing in vitro and in vivo.

The ability of 5-aminolaevulinic acid and some of its esterified derivatives to induce porphyrin accumulation has been examined in CaNT murine mammary carcinoma cells growing in culture and as tumours in vivo. Topical or intravenous administration of 5-aminolaevulinic acid-esters to mice bearing subcutaneous tumours produced lower porphyrin levels in the tumour than an equimolar dose of 5-aminolaevulinic acid. Reducing the dose of intravenous hexyl- or benzyl-ALA and topical hexyl-5-aminolaevulinic acid resulted in a dose-dependent reduction in porphyrin accumulation. A number of normal tissues accumulated higher concentrations of porphyrins than tumour tissue following intravenous administration of 5-aminolaevulinic acid-esters. Esterase activity in these normal tissues was greater than that in tumour tissue. In contrast to the situation in vivo, all of the 5-aminolaevulinic acid-esters examined were at least as effective as 5-aminolaevulinic acid when applied to cloned CaNT cells in vitro, with the drug concentration required for maximum porphyrin accumulation varying with ester chain-length. Tumour cells growing in culture released esterase activity into the medium. These findings suggest that the efficacy of 5-aminolaevulinic esters may vary depending on the esterase activity of the target tissue, and suggest caution when interpreting the findings of in vitro studies using these and similar prodrugs.

Administration, Cutaneous↗
PubMed2002

Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group.

Topical photodynamic therapy (PDT) is effective in the treatment of certain non-melanoma skin cancers and is under evaluation in other dermatoses. Its development has been enhanced by a low rate of adverse events and good cosmesis. 5-Aminolaevulinic acid (ALA) is the main agent used, converted within cells into the photosensitizer protoporphyrin IX, with surface illumination then triggering the photodynamic reaction. Despite the relative simplicity of the technique, accurate dosimetry in PDT is complicated by multiple variables in drug formulation, delivery and duration of application, in addition to light-specific parameters. Several non-coherent and coherent light sources are effective in PDT. Optimal disease-specific irradiance, wavelength and total dose characteristics have yet to be established, and are compounded by difficulties comparing light sources. The carcinogenic risk of ALA-PDT appears to be low. Current evidence indicates topical PDT to be effective in actinic keratoses on the face and scalp, Bowen's disease and superficial basal cell carcinomas (BCCs). PDT may prove advantageous where size, site or number of lesions limits the efficacy and/or acceptability of conventional therapies. Topical ALA-PDT alone is a relatively poor option for both nodular BCCs and squamous cell carcinomas. Experience of the modality in other skin diseases remains limited; areas where there is potential benefit include viral warts, acne, psoriasis and cutaneous T-cell lymphoma. A recent British Photodermatology Group workshop considered published evidence on topical PDT in order to establish guidelines to promote the efficacy and safety of this increasingly practised treatment modality.

Aminolevulinic Acid↗
PubMed2002

The advantages of aminolevulinic acid photodynamic therapy in dermatology.

Photodynamic therapy (PDT) is being increasingly employed in the detection and treatment of malignant and non-malignant disease. This local technique uses a photosensitizing drug activated by light to generate cell death via the production of reactive oxygen species. This review describes the fundamental processes behind PDT, focussing on the use of 5-aminolevulinic acid (ALA). ALA itself is not a photosensitizing drug, but administration of exogenous ALA induces the build-up of the natural endogenous photosensitizer protoporphyrin IX (PpIX). This form of PDT has proved promising for the treatment of a number of dermatological indications. An overview of these current and potential applications of ALA-based PDT is presented, with emphasis on the advantages of the technique that make it especially suitable for skin conditions and the problem areas on which future research should be focussed.

Aminolevulinic Acid↗
PubMed2001

Field-deployable sniffer for 2,4-dinitrotoluene detection.

A field-deployable instrument has been developed to detect low-level 2,4-dinitrotoluene (2,4-DNT) vapors. The system is based on previously developed artificial nose technology and employs an array of sensory materials attached to the distal tips of an optical fiber bundle. Both semiselective and nonspecific, cross-reactive sensors were employed. Each sensor within the array responds differentially to vapor exposure so the array's fluorescence response patterns are unique for each analyte. The instrument is computationally "trained" to discriminate target response patterns from nontarget and background environments. This detection system has been applied to detect 2,4-DNT, an analyte commonly detected on the soil surface above buried 2,4,6-trinitrotoluene (TNT) land mines, in spiked soil and aqueous and ground samples. The system has been characterized and demonstrated the ability to detect 120 ppb 2,4-DNT vapor in blind (unknown) humidified samples during a supervised field test.

Carcinogens↗
PubMed2001

Biochemical and physiological evidence that bile acids produced and released by lake char (Salvelinus namaycush) function as chemical signals.

It has been hypothesized that faeces of juvenile lake char (Salvelinus namaycush) may contain chemical cues that mediate behaviour of conspecifics. However, our knowledge of bile acids naturally produced and released by fish is limited. Using HPLC, we fractionated bile acids produced and released by lake char and examined their stimulatory effectiveness using electro-olfactogram recordings. Taurocholic acid, taurochenodeoxycholic acid, taurooxocholanic acid, taurooxodeoxycholic acid 3alpha-sulphate, trace amounts of taurolithocholic acid and an unidentified sulphated bile steroid were found in bile and faeces. Bile acids were either taurine amidated or sulphated, or both. Lake char released an average of 4 nmol min(-1) bile acids per kilogram of body weight into their tank water. Urinary bile acids accounted for only a small portion of total bile acids released into water. Water and faeces contained higher proportion of taurochenodeoxycholic acid and sulphated bile acids (relative to taurocholic acid) than bile. The electro-olfactogram recordings demonstrated that bile acids released by lake char were detectable by their olfactory system at nanomolar concentrations, which is well below the levels of bile acids released into water. The exquisite olfactory sensitivity of lake char to water-borne bile acids released by their conspecifics is consistent with a role for these compounds as important chemical signals.

Animal Communication↗
PubMed2001

Vitamin and thyroid status in arctic grayling (Thymallus arcticus) exposed to doses of 3,3',4,4'-tetrachlorobiphenyl that induce the phase I enzyme system.

Induction of phase I biotransformation enzymes is recognized as a hallmark response in fish exposed to coplanar PCBs. Depletions of vitamins A and E and disrupted thyroid hormone and glandular structure secondary to this induction have not yet been examined in an arctic fish species. Arctic grayling were exposed to a single oral dose of 0 (control), 10, 100 or 1000 ng 3,3',4,4'-tetrachlorobiphenyl (TCB) g(-1) bodyweight, a contaminant found in most arctic fish. After 30 and 90 days of exposure, TCB concentrations in tissues, hepatic phase I activity (as ethoxyresorufin-O-deethylase (EROD)), plasma and tissue vitamin A and E concentrations, plasma thyroid hormone levels and thyroid glandular structure were examined. Total plasma osmolality, as an indicator of overall fish health was also monitored. TCB recovery in tissues was low and extremely variable, making comparisons between intended dose groups inappropriate. Therefore, correlation analysis between actual recovered TCB concentrations and biochemical responses was employed. Hepatic EROD activity correlated strongly with liver TCB concentrations. Liver concentrations of vitamin A were altered as a function of TCB concentrations and EROD activity, but plasma vitamin A status was not affected. Vitamin E was depleted by TCB accumulation in blood and EROD induction in liver of males only at 90 days postexposure. Thyroid hormones status and glandular structure were not affected by the short duration TCB exposures used in this experiment. TCB concentrations were correlated with an elevation in plasma osmolality. Results from this experiment indicate that the vitamin status and osmoregulation of arctic grayling exposed to TCB can be compromised. Further studies of field populations exposed to this type of contaminant are warranted.

Administration, Oral↗
PubMed2001

The use of thiamine and thiamine antagonists to investigate the etiology of early mortality syndrome in lake trout (Salvelinus namaycush).

Early mortality syndrome (EMS) is a non-infectious disease affecting lake trout and other salmonids in the Great Lakes and in inland lakes. It is characterised by loss of equilibrium, hyperexcitability, anorexia, and eventually death. EMS is associated with low thiamine and treatment of eggs or fry with thiamine-HCl eliminates symptoms and mortality. To verify the role of the active form of the vitamin as the prophylactic agent, we used thiamine pyrophosphate (TPP) to reverse EMS symptoms. We also investigated the ability of specific thiamine antagonists that either block TPP production or interfere with its function to induce EMS. When graded doses of TPP were administered to EMS-susceptible sac-fry, there was a dose-dependent reduction in EMS. The egg concentration of TPP that was associated with reduced EMS was similar to the threshold thiamine concentration found in feral lake trout stocks where EMS occurs. A thiamine deficient stock from Lake Ontario was very sensitive to the thiamine antagonist oxythiamine (OXY) with total mortality associated with developmental arrest occurring at an antagonist to thiamine molar ratio (ATR) above 7:1. The threshold ATR with OXY for development of EMS-like neurological signs in this stock was 1.6:1. In addition to EMS-like neurological signs, OXY caused dose-dependent increases in hydrocephalus, developmental arrest, and vitelline congestion in the Lake Ontario stock. These signs are consistent with those observed in feral fish exhibiting EMS. Much higher doses of antagonists were required (both pyrithiamine (PT) and OXY) to induce EMS-like clinical signs in the thiamine replete Lake Manitou stock. PT was a more potent inducer in this stock as the ATR associated with development of clinical signs was 111:1 for PT compared with 892:1 for OXY. These data provide experimental evidence supporting the hypothesis that a thiamine deficiency in the natural environment is the cause of EMS.

Animals↗
PubMed2001

Verteporfin: a milestone in opthalmology and photodynamic therapy.

During the past year, a photosensitiser named benzoporphyrin derivative (BPD) has been approved in 26 countries under the generic name verteporfin (Visudynetrade mark, Novartis), for the treatment of patients with a certain type of the wet form of age-related macular degeneration (AMD) by photodynamic therapy (PDT). AMD is the leading cause of blindness in the developed world, with approximately half a million new cases of the wet form per year. The approval of Visudynetrade mark therapy represents a major milestone in ophthalmology since AMD was previously untreatable by any modality which would preserve existing vision. It was also a milestone in the development of PDT, not only because it represented the first breakthrough in the use of PDT to treat an otherwise untreatable condition, but also because it represented the first mass market for a PDT treatment where prospects of a substantial financial return on many years of investment appear to be likely. In this article, we look at the background to the development of BPD, primarily for its use in AMD, but also in other applications.

Clinical Trials, Phase I as Topic↗
PubMed2001

Investigation of cross-resistance to a range of photosensitizers, hyperthermia and UV light in two radiation-induced fibrosarcoma cell strains resistant to photodynamic therapy in vitro.

Two distinct photodynamic therapy-resistant variants of the murine radiation-induced fibrosarcoma (RIF) cell line have been isolated. One strain displayed relative resistance over the parental RIF-1 strain to treatment with the porphyrin-based compound, polyhaematoporphyrin (PHP), whereas the other strain displayed relative resistance over the RIF-1 strain to treatment using the cationic zinc (II) pyridinium-substituted phthalocyanine (PPC). The PHP-resistant strain did not display cross-resistance to PPC-mediated treatment, and vice versa. In both PDT-resistant strains, the increased resistance could not be attributed to altered cellular growth rate, antioxidant capacity or intracellular sensitizer localization. The PHP-resistant strain displayed resistance to treatment with both short (1 h) and extended (16 h) sensitizer incubation periods, which may indicate that in this strain, the resistance has arisen through an alteration in a membrane component. Conversely, the PPC-resistant strain only displayed increased resistance over the parental cells to treatment involving the short drug incubation, which is likely to reflect the existence of a threshold effect caused by the alteration of an individual cellular target. Each resistant strain has been compared to the parental strain in terms of cellular sensitivity to treatment with a range of other photosensitizers, hyperthermia, UV light and the anticancer agent cis-diamminedichloroplatinum. The PHP-resistant strain exhibited crossresistance to photosensitization treatment using exogenously added protoporphyrin IX, and also to treatment with the anionic phthalocyanine sensitizers, zinc (II) tetrasulfonated phthalocyanine and zinc (II) tetraglycine-substituted phthalocyanine. The PPC-resistant strain did not display cross-resistance to any of the treatment strategies employed in this investigation. The results of this investigation indicate that there are at least two distinct mechanisms of PDT resistance in RIF cells, and that the mechanism of PHP resistance may, to some extent depend, upon the physical nature of the sensitizer molecule.

Animals↗
PubMed2001

Decreased efficiency of trypsinization of cells following photodynamic therapy: evaluation of a role for tissue transglutaminase.

Identifying the cellular responses to photodynamic therapy (PDT) is important if the mechanisms of cellular damage are to be fully understood. The relationship between sensitizer, fluence rate and the removal of cells by trypsinization was studied using the RIF-1 cell line. Following treatment of RIF-1 cells with pyridinium zinc (II) phthalocyanine (PPC), or polyhaematoporphyrin at 10 mW cm-2 (3 J cm-2), there was a significant number of cells that were not removed by trypsin incubation compared to controls. Decreasing the fluence rate from 10 to 2.5 mW cm-2 resulted in a two-fold increase in the number of cells attached to the substratum when PPC used as sensitizer; however, with 5,10,15,20 meso-tetra(hydroxyphenyl) chlorine (m-THPC) there was no resistance to trypsinization following treatment at either fluence rate. The results indicate that resistance of cells to trypsinization following PDT is likely to be both sensitizer and fluence rate dependent. Increased activity of the enzyme tissue-transglutaminase (tTGase) was observed following PPC-PDT, but not following m-THPC-PDT. Similar results were obtained using HT29 human colonic carcinoma and ECV304 human umbilical vein endothelial cell lines. Hamster fibrosarcoma cell (Met B) clones transfected with human tTGase also exhibited resistance to trypsinization following PPC-mediated photosensitization; however, a similar degree of resistance was observed in PDT-treated control Met B cells suggesting that tTGase activity alone was not involved in this process.

Animals↗
PubMed2001

5-Aminolaevulinic acid methyl ester transport on amino acid carriers in a human colon adenocarcinoma cell line.

The transport mechanisms of 5-aminolevulinic acid methyl ester (5-ALA-ME) have been studied in a human adenocarcinoma cell line (WiDr) by means of 14[C]-labeled 5-ALA-ME. The transport was found to be partly Na+ dependent, while the extracellular Cl- concentration did not affect the uptake. The transport of 5-ALA-ME into WiDr cells was dependent on the incubation temperature and was found to be completely blocked by the inhibitors of energy metabolism, 2-deoxyglucose and sodium azide. WiDr cells were treated with 10 mM of 14 different amino acids and the substrate specificity of the 5-ALA-ME transporter(s) was analyzed by treating the cells with 23 microM or 1 mM 14[C]-labeled 5-ALA-ME. The transport of 5-ALA-ME was found to be inhibited to the highest extent, i.e. about 60%, by the nonpolar amino acids L-alanine, L-methionine, L-tryptophan and glycine. The uptake of 5-ALA-ME followed an exponential decay with increasing concentration of glycine, reaching a maximum inhibition of uptake of 5-ALA-ME of 55%. Sarcosine, a specific inhibitor of system Gly, did not significantly inhibit 5-ALA-ME transport. In contrast to transport of 5-ALA, 5-ALA-ME does not seem to be taken up by system BETA transporters. In conclusion, the cellular uptake of 5-ALA-ME into WiDr cells seems to be due to active transport mechanisms, involving transporters of nonpolar amino acids.

Adenocarcinoma↗
PubMed2000

Constitutive death of platelets leading to scavenger receptor-mediated phagocytosis. A caspase-independent cell clearance program.

Apoptosis is a physiological program for the deletion of cells in which caspases govern events leading to safe clearance by phagocytes. However, a growing weight of evidence now suggests that not all forms of programmed cell death are caspase-dependent. We now report a complete and constitutive but caspase-independent program for the specific phagocytic clearance of intact effete platelets, anucleated blood cells of critical importance in health and disease. Platelets aged in vitro not only exhibited increased expression of proapoptotic Bak and Bax but also evidenced constitutive diminution of function such as decreased aggregation to ADP, which was accelerated by culture in the absence of plasma. This abrogation of cell function in plasma-deprived platelets was associated with morphological and biochemical features similar to those of granulocyte apoptosis, that is, cytoplasmic condensation, plasma membrane changes including exposure of phosphatidylserine and the granule protein P-selectin, and recognition by phagocyte scavenger receptors. However, and in contrast with constitutive death of other inflammatory blood cells by apoptosis, these events were not affected by caspase inhibitors, nor was there evidence of caspase-3 activation either by hydrolysis of analog peptide substrates or Western blot analysis, serving to emphasize that neither programmed cell death nor clearance by phagocytes need involve caspases.

Apoptosis↗